PPAR Agonists Promote the Differentiation of Porcine Bone Marrow Mesenchymal Stem Cells into the Adipogenic and Myogenic Lineages.
The aim of this work was to evaluate the effect of PPAR agonists on the differentiation and metabolic features of porcine mesenchymal stem cells induced to the adipogenic or myogenic lineages. Bone marrow MSCs from neonate pigs were isolated and identified by cell proliferation, cell surface markers or the gene expression of stem cells (CD44, CD90, CD105 or Oct4 and Nanog, respectively). Cells were differentiated into adipose or muscle cells and treated with the PPAR agonists; adipogenic and myogenic differentiation was promoted by adding these compounds. The expression of PPARγ (an adipose marker) and MyoD1 and MyHC (muscle markers), metabolic changes and expression levels of metabolic enzymes involved in glycolysis, lipogenesis, lipolysis and the pentose phosphate pathway were tested by qPCR. MSCs from neonate pigs exhibited high proliferation and were positive for CD44, CD90 and CD105 markers and Oct4 and Nanog expression. The treatment that promoted the highest expression of PPARγ was 50 µM of conjugated linoleic acid (CLA) c9 t11 (6.44 ± 0.69-fold, p ≤ 0.0001) in the adipose differentiation, and upregulation of HX2, ACCAα, ATGL, LPL and G6DP (p ≤ 0.0001) and downregulation of PFK and ACCAβ (p ≤ 0.0001) were found. For muscle differentiation, the best treatment was 50 µM of CLA c10 t12 (59.72 ± 4.72-fold, p ≤ 0.0001), and metabolic changes were upregulation of PFK, ACCAβ, G6DP, CPT1 and PPARβ/δ (p ≤ 0.0001), but no effect was observed with HX2 and ACCAα (p ≥ 0.05). Our results suggest that differentiated cells exhibit a typical cell lineage metabolism and higher efficiencies both in anabolism and catabolism.


Dynamical Structure of a Traditional Amazonian Social Network.
Reciprocity is a vital feature of social networks, but relatively little is known about its temporal structure or the mechanisms underlying its persistence in real world behavior. In pursuit of these two questions, we study the stationary and dynamical signals of reciprocity in a network of manioc beer (Spanish: chicha; Tsimane': shocdye') drinking events in a Tsimane' village in lowland Bolivia. At the stationary level, our analysis reveals that social exchange within the community is heterogeneously patterned according to kinship and spatial proximity. A positive relationship between the frequencies at which two families host each other, controlling for kinship and proximity, provides evidence for stationary reciprocity. Our analysis of the dynamical structure of this network presents a novel method for the study of conditional, or non-stationary, reciprocity effects. We find evidence that short-timescale reciprocity (within three days) is present among non- and distant-kin pairs; conversely, we find that levels of cooperation among close kin can be accounted for on the stationary hypothesis alone.


[Evaluation of the role of chemotherapy adjuvant to surgery in patients with cancer of the ovary, 1st stage].
The paper discusses the results of a retrospective analysis of the data on the evaluation of the efficacy of chemotherapy as an adjuvant to surgery performed in 167 patients with stage I ovarian cancer who were treated at the Institute and Oncological Dispensary in the city of Gomel in 1963-1979. The evaluation was based on the comparison of 5-year survival rates and the frequency of recurrences in the following three study groups: surgery, surgery + chemotherapy and surgery + chemotherapy + prophylactic chemotherapy. It was found that chemotherapy courses given within 2.5-3 years after primary treatment are followed by a nearly two-fold (1.9) drop in recurrence frequency and a 16.6% increase in 5-year survival.


The BRICHOS domain, amyloid fibril formation, and their relationship.
Amyloid diseases are defined by tissue deposition of insoluble, fibrillar β-sheet polymers of specific proteins, but it appears that toxic oligomeric species rather than the fibrils are the main cause of tissue degeneration. Many proteins can form amyloid-like fibrils in vitro, but only ~30 proteins have been found to cause mammalian amyloid disease, suggesting that physiological mechanisms that protect against amyloid formation exist. The transmembrane region of lung surfactant protein C precursor (proSP-C) forms amyloid-like fibrils in vitro, and SP-C amyloid has been found in lung tissue from patients with interstitial lung disease (ILD). ProSP-C contains a BRICHOS domain, in which many ILD-associated mutations are localized, and the BRICHOS domain can prevent SP-C from forming amyloid-like fibrils. Recent data suggest that recombinant BRICHOS domains from proSP-C and Bri2 (associated with familial dementia and amyloid formation) interact with peptides with a strong propensity to form β-sheet structures, including amyloid β-peptide associated with Alzheimer's disease. Such interactions efficiently delay formation of fibrils and oligomers. The BRICHOS domain is defined at the sequence level and is found in ~10 distantly related proprotein families. These have widely different or unknown functions, but several of the proteins are associated with human disease. Structural modeling of various BRICHOS domains, based on the X-ray structure of the proSP-C BRICHOS domain, identifies a conserved region that is structurally complementary to the β-sheet- and/or amyloid-prone regions in the BRICHOS domain-containing proproteins. These observations make the BRICHOS domain the first example of a chaperone-like domain with specificity for β-prone regions.


Transmission of Er:YAG laser through different dental ceramics.
The aim of this study was to determine the erbium-doped yttrium aluminum garnet (Er:YAG) laser transmission ratio through different dental ceramics with different thicknesses. Laser debonding procedure of adhesively luted all-ceramic restorations is based on the transmission of laser energy through the ceramic and the ablation of resin cement, because of the transmitted laser energy. Five different dental ceramics were evaluated in this study: sintered zirconium-oxide core ceramic, monolithic zirconium-oxide ceramic, feldspathic ceramic, leucite-reinforced glass ceramic, and lithium disilicate-reinforced glass ceramic. Two ceramic discs with different thicknesses (0.5 and 1 mm) were fabricated for each group. Ceramic discs were placed between the sensor membrane of the laser power meter and the tip of the contact handpiece of an Er:YAG laser device with the aid of a custom- made acrylic holder. The transmission ratio of Er:YAG laser energy (500 mJ, 2 Hz, 1 W, 1000 μs) through different ceramic discs was measured with the power meter. Ten measurements were made for each group and the results were analyzed with two way analysis of variance (ANOVA) and Tukey honestly significant difference (HSD) tests. The highest transmission ratio was determined for lithium disilicate-reinforced ceramic with 0.5 mm thickness (88%) and the lowest was determined for feldspathic ceramic with 1 mm thickness (44%). The differences among the different ceramics and between the different thicknesses were significant (p<0.05). Ceramic type and thickness should be taken into consideration to adjust the laser irradiation parameters during laser debonding of adhesively luted all-ceramic restorations.


Modeling of Pharmaceutical Biotransformation by Enriched Nitrifying Culture under Different Metabolic Conditions.
Pharmaceutical removal could be significantly enhanced through cometabolism during nitrification processes. To date, pharmaceutical biotransformation models have not considered the formation of transformation products associated with the metabolic type of microorganisms. Here we report a comprehensive model to describe and evaluate the biodegradation of pharmaceuticals and the formation of their biotransformation products by enriched nitrifying cultures. The biotransformation of parent compounds was linked to the microbial processes via cometabolism induced by ammonium-oxidizing bacteria (AOB) growth, metabolism by AOB, cometabolism by heterotrophs (HET) growth, and metabolism by HET in the model framework. The model was calibrated and validated using experimental data from pharmaceutical biodegradation experiments at realistic levels, taking two pharmaceuticals as examples, i.e., atenolol and acyclovir. Results demonstrated the good predictive performance of the established biotransformation model under different metabolic conditions, as well as the reliability of the established model in predicting different pharmaceutical biotransformations. The linear positive correlation between ammonia oxidation rate and pharmaceutical degradation rate confirmed the major role of cometabolism induced by AOB in the pharmaceutical removal. Dissolved oxygen was also revealed to be capable of regulating the pharmaceutical biotransformation cometabolically, and the substrate competition between ammonium and pharmaceuticals existed especially at high ammonium concentrations.


Grating-less, fiber-based oscillator that generates 25 nJ pulses at 80 MHz, compressible to 150 fs.
We report a passively mode-locked fiber-based oscillator that has no internal dispersion-compensating gratings. This design, which we believe to be the first of its kind, produces 25 nJ pulses at 80 MHz with the pulses compressible to 150 fs. The pulses appear to be self-similar and initial data imply that their energy is further scalable.


Comedo-like openings in melanoma.
We describe a case of melanoma with the presence of comedo-like openings at dermoscopy. These structures, typical of seborrheic keratosis, represent an uncommon finding in melanoma. We emphasize the importance of searching for specific dermoscopic criteria for melanocytic lesions during the examination of a pigmented lesion, despite possible observations of characteristic structures of non-melanocytic lesions, in order to increase the accuracy in the diagnosis of melanoma.


Plasma pyridoxine deficiency is related to increased psychological distress in recently bereaved homosexual men.
Previous research has demonstrated that a theoretical model including measures of life stressors, social support, and coping style significantly predicts psychological distress. This study tested plasma pyridoxine (vitamin B6) deficiency status as a predictor of overall psychological distress and specific mood states in this model, controlling for HIV-1 serostatus. Subjects included HIV-1+ (N = 76) and HIV-1- (N = 58) recently bereaved homosexual men. At baseline, subjects completed a battery of psychosocial questionnaires, together with a physical examination and venipuncture. The Profile of Mood States (POMS) provided measures of overall psychological distress as well as specific mood states. Pyridoxine deficiency status (a categorical measure of deficient vs. adequate status) was determined with a bioassay of erythrocyte aspartate aminotransferase activity. Pyridoxine deficiency was a significant predictor of increased overall psychological distress in this model, controlling for life stressors, social support, coping style, and HIV-1 serostatus. In post hoc analyses of specific mood state effects, pyridoxine deficiency status was significantly associated with increases in depressed, fatigued, and confused mood levels, but not with those of anxiety, anger, or vigor. These findings suggest that adequate pyridoxine status may be necessary to avert psychological distress in the setting of bereavement. Inasmuch as pyridoxine is a cofactor for 5-hydroxytryptophan decarboxylase--an enzyme in the biosynthesis pathway of serotonin--serotonin level in the brain is implicated as the mediating factor.


Quantification of Natural Growth of Two Strains of Mycobacterium Marinum for Translational Antituberculosis Drug Development.
The zebrafish infected with Mycobacterium marinum (M. marinum) is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis (M. tuberculosis) infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and MUSA , is studied over an extended period using an established model-based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm-derived strain E11 and human-derived strain MUSA were grown undisturbed up to 221 days and viability of cultures (colony forming unit (CFU)/mL) was determined by plating at different time points. Nonlinear mixed effects modeling using the MTP model quantified the bacterial growth, the transfer among fast, slow, and non-multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20-25 days for E11 and MUSA , respectively, followed by a decrease to a new plateau. Natural growth of both E11 and MUSA was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow-multiplying state, for MUSA in the fast-multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, whereas MUSA showed more aggressive growth behavior. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of antituberculosis drug development.


Population-level impact of loss on survivor mortality risk.
The loss of a loved one adversely affects the bereaved. Using data from the 2010 and 2012 waves of Health and Retirement Study (HRS), we estimate the risk for death in a 2-year span after the loss of a parent, spouse, or child for adults aged 50 to 70 years. A respondent with a loss was twice as likely to die when compared similarly aged persons with no loss (OR 2.32; 95 % CI 1.14, 5.30). Loss of either a parent (OR 1.93; 95 % CI 1.01, 4.07), or a child (OR 1.77; 95 % CI 1.08, 2.96) also increased respondent mortality. This elevated risk persists after adjustment for gender and other high-risk health conditions. Any physical activity reduces survivor death rates during this critical period by more than 85 %.


[Endoprosthetic management of patients with hip arthrodesis].
Purpose of this retrospective study was to investigate the long-term results of total hip replacement in patients with hip arthrodesis. Between 1976 and 1986 conversion of a earlier performed arthrodesis of the hip to total hip replacement was carried out in a total of 20 patients. 15 of these have been followed up postoperatively for an average of 15.7 years. The main preoperative symptoms were pain affecting the lumbar spine, the ipsilateral knee and/or both hip joints. In two cases, the arthrodesis has fractured. With the exception of one female patient, all the patients expressed satisfaction with the postoperative results, pain having been alleviated or eliminated. The difference in leg length presenting preoperatively in 12 patients was partly or completely equalized in ten cases. Specific physiotherapy over a period of several months resulted in an appreciable increase in muscular power in all patients. Postoperatively ten patients had a slight, five a pronounced limp, while 11 patients needed a walking aid. Recurrent dislocations occurred in one patient. We observed one aseptic loosening of the cup after 10 years. The results of the study show that conversion of surgically ankylosed hip joints to total hip replacement makes good sense. Provided that the indication is established with care, this major surgical procedure represents a suitable method, not only of improving the patient's quality of life, but also, and in particular, of at least appreciably improving the symptoms developing after hip arthrodesis. There seems no increased rate of aseptic implant loosening.


Mating behavior and its morphological correlates in two color morphs of Girardinus metallicus (Pisces: Poeciliidae), a species previously thought not to exhibit courtship display.
Girardinus metallicus is a Cuban poeciliid fish whose social behavior has been little studied. The only account involves a colorless morph that is sexually monochromatic and does not exhibit courtship display. We describe the behavior of two other morphs (black and yellow) that exhibit sexual dichromatism. We observed courtship displays in black but not yellow males. Contrary to the pattern in most poeciliids, black males exhibit long gonopodia and courtship; typically, longer gonopodia evolve in species without courtship, because they facilitate coercive mating but circumvent female choice. We focused on the black morph to address whether morphological traits are favored by sexual selection. Larger males with longer gonopodia courted and attempted copulations more often. Black area was not associated with intersexual interactions, but was positively associated with aggressiveness. Dominant males attempted more copulations, consistent with the idea that black coloration may be a badge of status. Black males may possess long gonopodia because the gonopodium itself is a target of female choice. However, there was no difference in gonopodium length between black and yellow males, although the latter do not court. We discuss processes that may maintain the polymorphism and prospects for future studies in this intriguing system.


Depression, distress and self-efficacy: The impact on diabetes self-care practices.
The prevalence of type 2 diabetes is increasing in Malaysia, and people with diabetes have been reported to suffer from depression and diabetes distress which influences their self-efficacy in performing diabetes self-care practices. This interviewer administered, cross sectional study, conducted in the district of Hulu Selangor, Malaysia, involving 371 randomly selected patients with type 2 diabetes, recruited from 6 health clinics, aimed to examine a conceptual model regarding the association between depression, diabetes distress and self-efficacy with diabetes self-care practices using the partial least square approach of structural equation modeling. In this study, diabetes self-care practices were similar regardless of sex, age group, ethnicity, education level, diabetes complications or type of diabetes medication. This study found that self-efficacy had a direct effect on diabetes self-care practice (path coefficient = 0.438, p<0.001). Self-care was not directly affected by depression and diabetes distress, but indirectly by depression (path coefficient = -0.115, p<0.01) and diabetes distress (path coefficient = -0.122, p<0.001) via self-efficacy. In conclusion, to improve self-care practices, effort must be focused on enhancing self-efficacy levels, while not forgetting to deal with depression and diabetes distress, especially among those with poorer levels of self-efficacy.


Carpe Diem: time to seize the opportunity for cancer prevention.
In his plea for increased resources to implement cancer prevention strategies, Graham Colditz, MD, states that half or more of cancers in the U.S. and other high-income countries are preventable with information already available. He describes the data-driven possibilites: screening, vaccination, exercise, smoking cessation, sun protection, safe sexual practices, and moderate to no alcohol intake, as well as approaches to implement these strategies and makes a compelling case for using resources for this purpose. Dr. Colditz is Associate Director of Prevention and Control in the Alvin J. Siteman Cancer Center, and Niess-Gain Professor in the Department of Surgery at the Washington University School of Medicine. He received his PhD in epidemiology from Harvard University, and his Internal Medicine Training at the Royal Brisbane Hospital in Australia. Dr. Colditz has an enormous volume of publications, with over 800 original research articles. He has worked to identify lifestyle and environmental factors that affect people's health, and to develop and teach cancer prevention strategies at the individual and community levels. His research also powers a website-www.yourdiseaserisk.wustl.edu-that helps people assess their risk of developing cancer, diabetes and other diseases as well as suggesting ways to lead longer, healthier lives. His work is inspirational in combining excellent scientific investigation with dedication to making results available and useful to non-scientists. Gini F. Fleming, MD, Cancer Education Committee Chair.


Organization of intramembrane particles in freeze-cleaved gap junctions of rat graafian rollicles: optical-diffraction analysis.
Gap junctions were identified in the membrana granulosa and cumulus oophorus, and between cells of the internal theca, of the preovulatory rat follicle. In replicas of freeze fractured follicles, the A face presented clusters of closely packed intramembrane particles, 7--9 nm in diameter, forming a mosaic pattern, while the B face showed a similar pattern of small pits. Optical diffraction analysis of these electron micrographs revealed that both the intramembrane particles and the corresponding pits were organized in hexagonal lattices with centre-to-centre spacing of 9-10 nm. In small junctions (up to 0.4 mum in diameter), both A and B faces generally consisted of a single lattice, while large junctions (0.5-2 mum) contained multiple lattices differing in orientation. Occasionally intramembrane particles and pits were more loosely arranged throughout the junctional area and failed to show a hexagonal pattern. Both granulosa and thecal cells often contained intracellular vesicles resembling annular junctions. These contained intramembrane particles whose assembly resembled that of the gap junctions with regard to periodicity and lattice organization. Examination of thin section of thin sections suggested that small gap junctions occur also between cytoplasmic processes of coronal cells and the oolemma. No tight junctions were detected between granulosa cells and between thecal cells.


Long-term visual pathology in children with significant perinatal complications.
Eye research in infants who experience significant perinatal complications has been restricted to evaluation of structural ocular disease and spatial vision, and results show that these aspects of vision are at increased risk for abnormal or delayed development. To expand upon previous work, a battery of 17 vision tests was employed to assess, comprehensively, long-term outcome of functional vision. Seventy-six children (38 males, 38 females), between the corrected ages of 2 years 11 months and 10 years 2 months (mean 6y 6mo) with various significant complications (e.g. very preterm birth, bronchopulmonary dysplasia, intraventricular hemorrhage) were compared to normally developing, age-matched control children (n = 61; mean age 7y 1mo) on measures of visual acuity, contrast sensitivity, stereoacuity, peripheral vision, color vision, astigmatism, and binocular alignment. Results showed that at-risk children had more test results that fell within the suspect or abnormal range. At-risk children also had a slightly higher incidence of ocular disorders (e.g. strabismus) and refractive error. These data imply that children who experienced significant perinatal risk factors are at risk for long-term deficits of functional vision. However, most of these deficits appear to be relatively mild.


Functional disruption in the organization of the brain for reading in dyslexia.
Learning to read requires an awareness that spoken words can be decomposed into the phonologic constituents that the alphabetic characters represent. Such phonologic awareness is characteristically lacking in dyslexic readers who, therefore, have difficulty mapping the alphabetic characters onto the spoken word. To find the location and extent of the functional disruption in neural systems that underlies this impairment, we used functional magnetic resonance imaging to compare brain activation patterns in dyslexic and nonimpaired subjects as they performed tasks that made progressively greater demands on phonologic analysis. Brain activation patterns differed significantly between the groups with dyslexic readers showing relative underactivation in posterior regions (Wernicke's area, the angular gyrus, and striate cortex) and relative overactivation in an anterior region (inferior frontal gyrus). These results support a conclusion that the impairment in dyslexia is phonologic in nature and that these brain activation patterns may provide a neural signature for this impairment.


Expression of inflammatory markers in women with perinatal depressive symptoms.
Perinatal depression affects 10-20% of women and is associated with poor outcomes for mother and child. Inflammation is associated with depression in non-pregnant adults. Perinatal depression and inflammation in pregnancy are independently associated with morbidities including obesity, gestational diabetes, preeclampsia, and preterm birth. The role of inflammation in perinatal depression has received little attention. We hypothesized an association between self-reported perinatal depressive symptoms and serum inflammatory biomarkers TNF-α, IL-6, IL-1β, and CRP. 110 healthy gravidas were recruited in third trimester from an academic medical center, with a baseline study visit at a mean of 32.5 (SD ± 1.8) weeks gestational age. Sixty-three participants completed the Edinburgh Postnatal Depression Scale (EPDS) and provided demographic information and serum samples upon enrollment and at 3 and 6 months postpartum. Serum inflammatory markers were quantified by multiplex array. Multiple linear mixed effects models were used to evaluate trends of biomarkers with the EPDS score in the third trimester of pregnancy and the postpartum period. Elevated serum TNF-α was associated with lower EPDS total score (β = - 0.90, p = 0.046) after adjusting for demographics and medication use. In contrast, IL-6, CRP, and IL-1β did not demonstrate statistically significant associations with depressive symptoms by the EPDS in either crude or adjusted models. Study findings showed no association or an inverse (TNF-α) association between inflammatory markers and perinatal depressive symptoms. Relevant literature evaluating a role for inflammation in depression in the unique context of pregnancy is both limited and inconsistent, and further exploration is merited.


A case-control study of multiple system atrophy in Korean patients.
A few case-control studies of multiple system atrophy (MSA) have been reported in Western populations. In this study, we included various epidemiological factors to evaluate whether the risk factors for MSA differed in Korean and Western populations. A total of 100 consecutive MSA patients and 104 controls at two referral hospitals participated. Information was obtained through face-to-face interviews using a structured questionnaire: history of living area, occupational history, food habits, alcohol and tobacco consumption, and use of drugs. Odds ratios and 95% confident intervals (OR [95% CI]) were computed using logistic regression. The multivariate logistic regression analysis revealed that use of antihypertensive medication (OR = 0.30 [0.12-0.78]) and vitamins (OR = 0.30 [0.14-0.64]) and consumption of meat and poultry (OR = 0.27 [0.13-0.56]) were associated with decreasing risk for MSA, whereas use of herbal medications (OR = 3.17 [1.28-7.84]) was associated with increasing risk for MSA. In univariate analysis adjusted for age, sex, education level, and recruitment center, use of aspirin (OR = 0.21 [0.07-0.61]) and coffee consumption (OR = 0.44 [0.23-0.84]) were significantly less frequent in MSA patients than in controls, whereas heavy smoking (≥40 pack-years) was significantly more prevalent in MSA patients than in controls (OR = 3.44 [1.05-11.23]). There was no difference in living area, participation in farming, or exposure to agrichemicals and solvents between groups. This study showed that MSA in Korea is characterized by risk factors that are both similar to and different from those affecting Western populations and that herbal medicines constitute a new MSA risk factor for the Korean population.


Lynx: a database and knowledge extraction engine for integrative medicine.
We have developed Lynx (http://lynx.ci.uchicago.edu)--a web-based database and a knowledge extraction engine, supporting annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Its underlying knowledge base (LynxKB) integrates various classes of information from >35 public databases and private collections, as well as manually curated data from our group and collaborators. Lynx provides advanced search capabilities and a variety of algorithms for enrichment analysis and network-based gene prioritization to assist the user in extracting meaningful knowledge from LynxKB and experimental data, whereas its service-oriented architecture provides public access to LynxKB and its analytical tools via user-friendly web services and interfaces.


Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice.
Adhesive interactions between leukocytes and endothelial cells are characteristic of the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor-deficient mice on an atherogenic diet. The main purpose of this study is to examine the role of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice. METHODDS AND RESULTS: We intercrossed P-selectin-deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE(-/-) P(+/+)) and without P-selectin (apoE(-/-) P(-/-)) that were fed normal mouse chow. At 4 months of age, apoE(-/-) P(-/-) mice had 3. 5-fold smaller aortic sinus lesions than apoE(-/-) P(+/+) mice. These were limited to fatty streaks in the apoE(-/-) P(-/-) mice, whereas 70% of apoE(-/-) P(+/+) lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE(-/-) P(+/+) animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin-positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE(-/-) P(-/-) mice. In the aortic sinus, the lesions of the apoE(-/-) P(-/-) mice were 2.6-fold smaller and less calcified. P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice.


Effects of metabolic acidosis on viability of cells exposed to anoxia.
The effects of metabolic acidosis were examined in isolated rat hepatocytes under substrate-free oxygenated or anoxic conditions. Lowering extracellular pH to 6.6 under aerobic conditions had no deleterious effects on the cells as determined by trypan blue exclusion, lactate dehydrogenase (LDH) release, cellular K+ and Ca2+ content, and ability to increase ATP levels after nutrients and adenosine were added to media. Cytosolic pH was measured in aerobic cells at varying extracellular pH using 6-carboxyfluorescein. By using values for cytosolic pH obtained in this manner together with 5,5-dimethyl[2-14C]oxazolidine-2,4-dione (DMO) distribution data, a method was derived for determining intramitochondrial pH. The pH gradient across the mitochondrial membrane was found not to change with a decrease in extracellular pH from 7.4 to 6.9. At pH 6.9 hepatocytes were protected against anoxic injury as compared with cells incubated at pH 7.5 or 6.6. This protection was manifested by a decrease in vital dye uptake and LDH release, maintenance of higher cellular K+ content, less stimulation of respiration with succinate, improved recovery of ATP levels after return to an oxygenated nutrient environment, and maintenance of normal cellular Ca2+ content after reoxygenation. Recovery of cellular ATP content was independent of ATP levels, total adenine nucleotide pool, and energy charge ratio at the end of the anoxic period. Measurement of cytoplasmic pH in anaerobic cells by [14C]DMO distribution showed progressive cellular acidification with lowering of extracellular pH. The protective effects observed at pH 6.9 are not unique to hepatocytes since isolated renal cortical tubules exposed to anoxia have improved ATP levels on reoxygenation at this pH when compared with tubules incubated at pH 7.5.


Monte Carlo simulation of electron cones used in electron beam therapy.
A Siemens Mevatron KV2 accelerator installed at the Royal Adelaide Hospital employs cylindrical solid-walled electron cones for some electron collimation. The cones being used at present result in treatment fields that do not always conform with the International Electrotechnical Commission (IEC) Standards (particularly at high energies). The aim of this project was to simulate the existing cones using Monte Carlo methods in order to evaluate potential cone modifications required to overcome the field irregularities. Simulations were performed using the EGS4 (Electron Gamma Shower version 4, distribution II) Monte Carlo code installed on a DEC Alpha workstation at the University of South Australia. To rigorously simulate the existing electron cones it was necessary to also simulate various components within the treatment head of the linear accelerator. Results of simulations for existing cones were found to be consistent with experimental data. (obtained from Royal Adelaide Hospital beam quality assurance measurements). Two proposed changes to the cones were then simulated and the effects of these alterations were assessed. This study has shown how treatment head simulation techniques can be used to assess the changes in dose distribution that result from alterations to the treatment head and accessories. Within practical engineering constraints modifications to an existing electron collimation system were proposed and theoretically evaluated.


Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value.
Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.


[Regenerative activity of muscle allografts and thymus status during long-term laser exposure of adrenals and homoplasty region prior to transplantation].
Cross allografting of both gastrocnemius muscles between intact rats and those with the adrenal and right shin preirradiated with a He-Ne laser (632.8 nm, 2.5-3.0 mW/cm2, 10 sessions within 14 days with the cumulative dose being 15-18 J/cm2 per rat). By the time of grafting, the adrenal activity decreased while the activity of thymus decreased. As a result, the allogenic muscle tissue was resorbed in the irradiated rats, particularly, in the right irradiated shin. At the same time, reinnervation of the grafts with a certain amount of survived allogenic muscle tissue was more active in the right irradiated shin as compared to the left intact one. Survival of the donor muscle tissue and its improved reinnervation was observed in a higher proportion of grafts in the intact rats. The allografts from the right preirradiated shin of animals with irradiated adrenal proved to be more viable as compared to the left intact shin.


Effect of tip shape on capacitance determination accuracy in scanning capacitance microscopy.
We present an analysis of the measurement error caused by the stray field of scanning capacitance microscope probes of various shapes. Cylindrical islands and wells of varying radius and height or depth, in both conducting surfaces and structures containing dielectric films, were used as test features for modelling. The results show that high accuracy and good contrast of small details are contradictory requirements. Probes with small radius of curvature of the tip apex yield smaller errors on features with small diameter but larger ones on features with large diameter than tips with large radius of curvature. The stray electrostatic field causes large errors, which are exceptionally severe with microfabricated probes. Contrary to general belief, differential measurements, based on modulation of the probe/sample separation or of the width of depletion layer in semiconductors, do not reduce the effect of the stray field significantly. For best results, the probe should be shielded as close to the tip apex as possible. In the case of microfabricated probes, at least the side of the cantilever facing the sample should be shielded.


European List of Essential Medicines for Medical Education: a protocol for a modified Delphi study.
Junior doctors are responsible for a substantial number of prescribing errors, and final-year medical students lack sufficient prescribing knowledge and skills just before they graduate. Various national and international projects have been initiated to reform the teaching of clinical pharmacology and therapeutics (CP&T) during undergraduate medical training. However, there is as yet no list of commonly prescribed and available medicines that European doctors should be able to independently prescribe safely and effectively without direct supervision. Such a list could form the basis for a European Prescribing Exam and would harmonise European CP&T education. Therefore, the aim of this study is to reach consensus on a list of widely prescribed medicines, available in most European countries, that European junior doctors should be able to independently prescribe safely and effectively without direct supervision: the European List of Essential Medicines for Medical Education. This modified Delphi study will recruit European CP&T teachers (expert group). Two Delphi rounds will be carried out to enable a list to be drawn up of medicines that are available in ≥80% of European countries, which are considered standard prescribing practice, and which junior doctors should be able to prescribe safely and effectively without supervision. The study has been approved by the Medical Ethics Review Committee of VU University Medical Center (no. 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education (approved project no. NVMO-ERB 2020.4.8). The European List of Essential Medicines for Medical Education will be presented at national and international conferences and will be submitted to international peer-reviewed journals. It will also be used to develop and implement the European Prescribing Exam.


[Thoracic hydatidosis. Our experience in the last 15 years].
Hydatidosis in Spain has been a relevant public health problem which has been partly solved due to the implementation of different preventive programs. In this work the thoracic hydatidosis cases diagnosed at our hospital during the last 15 years are reported. Forty patients with thoracic hydatidosis are analyzed. Most of them had pulmonary hydatidosis (32), 14 had liver and lung cysts, and in eight cases of thoracic hydatidosis there was no pulmonary involvement; eight patients had been operated previously because of hydatidosis. A discussion follows of the epidemiologic, clinical and radiologic characteristics, as well as laboratory data, endobronchial changes, diagnostic cost/effectiveness of bronchoscopy when performed, and results after surgery. To remark the high percentage of complicated hydatidosis and uncommon locations, seven cases of multiple hydatidosis (two of them with cardiac involvement), five cases had hepato-thoracic communication, three with chest wall involvement, and one with exclusive cardiac involvement, as well as one case of calcified pulmonary hydatidosis. In most patients (37), treatment was surgery with a low number of complications at post-surgery (3). Three relapses were noted at follow-up.


A rapid and improved method for the detection of Vibrio parahaemolyticus and Vibrio vulnificus strains grown on hydrophobic grid membrane filters.
DNA probe-based detection methods were developed and characterized as an alternative to time-consuming and less specific conventional protocols. Digoxigenin-labeled probes were prepared by polymerase chain reaction amplification of the targeted sequences in the specific amplicons generated from genomic DNA. Specific probes with high yields were generated for the detection of the tlh gene of Vibrio parahaemolyticus and the cth gene of V. vulnificus. Colony (Southern) hybridization analyses were carried out using hydrophobic grid membrane filters (HGMFs) to allow biotype-specific differentiation of the two species. Eight strains of V. vulnificus and five strains of V. parahaemolyticus, including one standard (ATCC) strain of each biotype, were examined. Colony lysis, hybridization, and nonradioactive detection parameters were optimized for identification of the target biotypes arranged on the same HGMF and also on a conventional nylon membrane, thereby confirming the specificity of the probes and the comparative usefulness of the HGMFs. The experimental procedure presented here can be completed in 1 day. The protocol was designed specifically to identify the target Vibrio spp. and could potentially be used for the enumeration and differentiation of V. parahaemolyticus and V. vulnificus in foods.


High crossectomy without vascular sectioning vs classic saphenectomy. Randomized clinical trial: analysis of recurrent varicose veins.
This study was designed with the aim of defining a new surgical procedure for varicose veins and for comparison with classic crossectomy in terms of reducing the recurrence rate of varicose veins. Double-blind randomized clinical trial. For easy access, we selected 150 patients who came to the Phlebology Consultation Unit meeting inclusion criteria. With their informed consent, they were included in a study group using random table numbers. Group 1: (CS) Classic saphenectomy, 75 patients. Group 2: (HCWVS) High crossectomy without vascular sectioning. Both groups were monitorised at 12 and 24 months by Eco-Doppler study. The incidence of varicose vein recurrence at 12 month follow-up was 69.3% in the group of patients undergoing CS, while in the group receiving HCWVS it was 29.3% (p <0.0001). These differences, though minor, remained statistically significant at 24 months of evolution (76% vs. 48%, p = 0.0004). The most common recurrence type was type I, with statistically significant differences at 12 and 24 months. We believe that saphenectomy with crossectomy without vascular sectioning is the appropriate procedure to treat varicose veins, reducing type 1 or reticular relapse rate and maintaining the principles of classic surgery to reduce type 2 or truncular recurrence rate. This technique should be implemented with procedures based on saphenous sclerosis with foam art the saphenous femoral junction, in order to assess the recurrence rate of type 2 or truncular varicose veins.


The effects of subdivision on the genetic divergence of populations and species.
An island model of migration is used to study the effects of subdivision within populations and species on sample genealogies and on between-population or between-species measures of genetic variation. The model assumes that the number of demes within each population or species is large. When populations (or species), connected either by gene flow or historical association, are themselves subdivided into demes, changes in the migration rate among demes alter both the structure of genealogies and the time scale of the coalescent process. The time scale of the coalescent is related to the effective size of the population, which depends on the migration rate among demes. When the migration rate among demes within populations is low, isolation (or speciation) events seem more recent and migration rates among populations seem higher because the effective size of each population is increased. This affects the probability of reciprocal monophyly of two samples, the chance that a gene tree of a sample matches the species tree, and relative likelihoods of different types of polymorphic sites. It can also have a profound effect on the estimation of divergence times.


Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1.
Thrombospondin (TSP)1 is a tumor suppressor with activity that is associated with its ability to inhibit neovascularization. Previous studies have mapped this antiangiogenic activity to the type 1 repeats and the amino-terminal portion of the molecule within the procollagen-like domain. The present study was performed to investigate the ability of TSP-1 and peptides derived from the type 1 repeats to inhibit retinal angiogenesis. TSP-1 and peptides with tryptophan-rich, heparin-binding sequences and transforming growth factor (TGF)-beta1 activation sequences were evaluated in two models of retinal angiogenesis: a retinal explant assay and a rat model of retinopathy of prematurity (ROP). Platelet-derived TSP-1 inhibited angiogenesis in both experimental models. Peptides from the native TSP-1 sequence, which contained both the tryptophan-rich repeat and the TGF-beta1 activation sequence, were the most potent inhibitors of endothelial cell outgrowth in the retinal explant assay. In contrast, a peptide containing only the tryptophan-rich, heparin-binding sequence was most active in inhibiting neovascular disease in the rat ROP model. These results indicate that the type 1 repeats of TSP-1 contain two subdomains that may independently influence the process of neovascularization, and that peptides derived from these type 1 repeats may be promising pharmacologic agents for treatment of retinal angiogenesis.


Multiple translational control sequences in the 5' leader of the chloroplast psbC mRNA interact with nuclear gene products in Chlamydomonas reinhardtii.
Translation of the chloroplast psbC mRNA in the unicellular eukaryotic alga Chlamydomonas reinhardtii is controlled by interactions between its 547-base 5' untranslated region and the products of the nuclear loci TBC1, TBC2, and possibly TBC3. In this study, a series of site-directed mutations in this region was generated and the ability of these constructs to drive expression of a reporter gene was assayed in chloroplast transformants that are wild type or mutant at these nuclear loci. Two regions located in the middle of the 5' leader and near the initiation codon are important for translation. Other deletions still allow for partial expression of the reporter gene in the wild-type background. Regions with target sites for TBC1 and TBC2 were identified by estimating the residual translation activity in the respective mutant backgrounds. TBC1 targets include mostly the central part of the leader and the translation initiation region whereas the only detected TBC2 targets are in the 3' part. The 5'-most 93 nt of the leader are required for wild-type levels of transcription and/or mRNA stabilization. The results indicate that TBC1 and TBC2 function independently and further support the possibility that TBC1 acts together with TBC3.


The importance of prognosis in geriatric patients attending the emergency department: a comparison between two common short geriatric assessment tools.
The use of short geriatric tools in the emergency department (ED) is increasing, but the literature is still conflicting. The aim of this study is to compare the precision and the accuracy of two short geriatric assessment tools to predict mortality in a cohort of older patients attending the ED. A retrospective study was conducted including patients ≥ 65 years, attending the ED and transferred to a medical assessment unit from February to July 2022. Clinical Frailty Scale (CFS) and Brief Multidimensional Prognostic Index (Brief MPI) were administered. The association between Brief MPI and CFS and mortality was analysed via area under the curve (AUC) with its 95% confidence intervals (CIs), the C-statistics and a multivariate Cox's regression analysis, in the latter case reporting the data as hazard ratios (HRs) with their 95% CI. Among the 579 patients enrolled (mean age: 77 years), both Brief MPI and CFS showed a good accuracy in predicting mortality (AUC: 0.72; 95% CI: 0.61-0.83 for Brief MPI; 0.754; 95% CI: 0.65-0.83 for CFS). The discrimination of Brief MPI and CFS in predicting mortality was excellent, since the C-index of the Brief MPI was 0.85 and of CFS = 0.84. In the multivariate analysis, the risk for mortality was significantly increased for frailer subjects (HR 4.65; 95% CI: 1.45-15.00 for Brief MPI > 0.66; HR = 9.24; 95% CI: 1.16-76.90 for CFS > 6). Brief MPI and CFS showed a good accuracy/precision to predict mortality in older patients attending the ED. Considering that they are quick to perform, their introduction in ED clinical practice could be extremely helpful.


Postpartum Home Blood Pressure Monitoring: A Systematic Review.
To assess the effectiveness of postpartum home blood pressure (BP) monitoring compared with clinic-based follow-up and the comparative effectiveness of alternative home BP-monitoring regimens. Search of Medline, Cochrane, EMBASE, CINAHL, and ClinicalTrials.gov from inception to December 1, 2022, searching for home BP monitoring in postpartum individuals. We included randomized controlled trials (RCTs), nonrandomized comparative studies, and single-arm studies that evaluated the effects of postpartum home BP monitoring (up to 1 year), with or without telemonitoring, on postpartum maternal and infant outcomes, health care utilization, and harm outcomes. After double screening, we extracted demographics and outcomes to SRDR+. Thirteen studies (three RCTs, two nonrandomized comparative studies, and eight single-arm studies) met eligibility criteria. All comparative studies enrolled participants with a diagnosis of hypertensive disorders of pregnancy. One RCT compared home BP monitoring with bidirectional text messaging with scheduled clinic-based BP visits, finding an increased likelihood that at least one BP measurement was ascertained during the first 10 days postpartum for participants in the home BP-monitoring arm (relative risk 2.11, 95% CI 1.68-2.65). One nonrandomized comparative study reported a similar effect (adjusted relative risk [aRR] 1.59, 95% CI 1.36-1.77). Home BP monitoring was not associated with the rate of BP treatment initiation (aRR 1.03, 95% CI 0.74-1.44) but was associated with reduced unplanned hypertension-related hospital admissions (aRR 0.12, 95% CI 0.01-0.96). Most patients (83.3-87.0%) were satisfied with management related to home BP monitoring. Home BP monitoring, compared with office-based follow-up, was associated with reduced racial disparities in BP ascertainment by approximately 50%. Home BP monitoring likely improves ascertainment of BP, which is necessary for early recognition of hypertension in postpartum individuals, and may compensate for racial disparities in office-based follow-up. There is insufficient evidence to conclude that home BP monitoring reduces severe maternal morbidity or mortality or reduces racial disparities in clinical outcomes. PROSPERO, CRD42022313075.


Assessing the Effects of Stocking Density on Turkey Tom Health and Welfare to 16 Weeks of Age.
Four levels of turkey tom stocking density (SD) (30, 40, 50, 60 kg/m2) were evaluated in two 16 week trials (n = 2,868 Nicholas Select). Poults were allocated to one of eight independently ventilated rooms per trial (6.71 × 10.06 m) based on final predicted body weight (two replicates per SD per trial). Room temperature, humidity, carbon dioxide and ammonia concentration were recorded throughout the trial; ventilation was adjusted to equalize air quality across treatments. Mobility (gait score, scale 0-5) was recorded at 12 and 16 weeks (20 birds per replicate). Footpad lesion score (scale 0-4), feather condition (scale 1-4), and cleanliness scores (scale 1-4) were recorded at 10 (Trial 2), 12, and 16 weeks of age (20 birds per replicate). Aggressive injury incidence was recorded daily for Trial 2. Stress (heterophil/lymphocyte ratio) was evaluated at 4, 12, and 16 weeks of age (15 birds per replicate). Behavior was recorded and scan sampled (field of view) at 12 (Trial 1), 14, and 16 weeks. Data were analyzed using regression analysis (linear, Proc Reg; quadratic, Proc RSReg) for relationships between the variables and SD. Differences were considered significant when p ≤ 0.05. Mobility and footpad lesions were negatively affected by increasing SD (linear) at 16 weeks only. Feather condition and cleanliness decreased linearly as SD increased at week 10, 12, and 16. The incidence of aggressive damage was higher as SD increased during week 4-8 (quadratic). Heterophil/lymphocyte ratios increased linearly at 4 weeks (similar trend at 12 weeks). Behavior was impacted at 12 weeks of age with standing behavior showing a quadratic response, and walking and total disturbance showing a linear decrease as SD increased. Resting, preening, and comfort behaviors increased linearly (14 weeks), while walking and strutting decreased linearly with increasing SD. Finally, at 16 weeks of age resting, standing, walking, feeding, and total disturbance responded quadratically while preening behavior increased linearly with increasing SD. Results suggest that increasing SD negatively impacts bird health and wellbeing through decreased mobility, increased footpad lesions, poorer feather condition and cleanliness, and behavioral changes, but that very low SD (30 kg/m2) may result in increased aggressive damage.


[Polycystic liver disease without autosomal dominant polycystic kidney disease].
Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.


Mass spectrometric identification of proteins and characterization of their post-translational modifications in proteome analysis.
High-throughput DNA sequencing has resulted in increasing input in protein sequence databases. Today more than 20 genomes have been sequenced and many more will be completed in the near future, including the largest of them all, the human genome. Presently, sequence databases contain entries for more than 425.000 protein sequences. However, the cellular functions are determined by the set of proteins expressed in the cell--the proteome. Two-dimensional gel electrophoresis, mass spectrometry and bioinformatics have become important tools in correlating the proteome with the genome. The current dominant strategies for identification of proteins from gels based on peptide mass spectrometric fingerprinting and partial sequencing by mass spectrometry are described. After identification of the proteins the next challenge in proteome analysis is characterization of their post-translational modifications. The general problems associated with characterization of these directly from gel separated proteins are described and the current state of art for the determination of phosphorylation, glycosylation and proteolytic processing is illustrated.


Laparoscopic cystogastrostomy for the treatment of pancreatic pseudocysts: a case report.
Pancreatic pseudocysts (PPs) are collections of pancreatic secretions that are lined by fibrous tissues and may contain necrotic debris or blood. The interventions including percutaneous, endoscopic or surgical approaches are based on the size, location, symptoms and complications of a pseudocyst. With the availability of advanced imaging systems and cameras, better hemostatic equipments and excellent laparoscopic techniques, most pseudocysts can be found and managed by laparoscopy. We describe a case of a 30-year-old male patient with a pancreatic pseudocyst amenable to laparoscopic cystogastrostomy. An incision was made through the anterior gastric wall to expose the posterior gastric wall in close contact with the pseudocyst using an ultrasonically activated scalpel. Then, another incision was made for cystogastrostomy to obtain complete and unobstructed drainage. The patient recovered well after operation and was symptom-free during a 6-mo follow-up, suggesting that laparoscopic cystogastrostomy is a safe and effective alternative to open cystogastrostomy for minimally invasive management of PPs.


Identification of attractive drug targets in neglected-disease pathogens using an in silico approach.
The increased sequencing of pathogen genomes and the subsequent availability of genome-scale functional datasets are expected to guide the experimental work necessary for target-based drug discovery. However, a major bottleneck in this has been the difficulty of capturing and integrating relevant information in an easily accessible format for identifying and prioritizing potential targets. The open-access resource TDRtargets.org facilitates drug target prioritization for major tropical disease pathogens such as the mycobacteria Mycobacterium leprae and Mycobacterium tuberculosis; the kinetoplastid protozoans Leishmania major, Trypanosoma brucei, and Trypanosoma cruzi; the apicomplexan protozoans Plasmodium falciparum, Plasmodium vivax, and Toxoplasma gondii; and the helminths Brugia malayi and Schistosoma mansoni. Here we present strategies to prioritize pathogen proteins based on whether their properties meet criteria considered desirable in a drug target. These criteria are based upon both sequence-derived information (e.g., molecular mass) and functional data on expression, essentiality, phenotypes, metabolic pathways, assayability, and druggability. This approach also highlights the fact that data for many relevant criteria are lacking in less-studied pathogens (e.g., helminths), and we demonstrate how this can be partially overcome by mapping data from homologous genes in well-studied organisms. We also show how individual users can easily upload external datasets and integrate them with existing data in TDRtargets.org to generate highly customized ranked lists of potential targets. Using the datasets and the tools available in TDRtargets.org, we have generated illustrative lists of potential drug targets in seven tropical disease pathogens. While these lists are broadly consistent with the research community's current interest in certain specific proteins, and suggest novel target candidates that may merit further study, the lists can easily be modified in a user-specific manner, either by adjusting the weights for chosen criteria or by changing the criteria that are included.


Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial.
Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting. To determine the efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction. Randomized, double-blind, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. The 1510 participants were cigarette smokers who were not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months. Participants were recruited through advertising. Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with a reduction target of 50% or more in number of cigarettes smoked by 4 weeks, 75% or more by 8 weeks, and a quit attempt by 12 weeks. Primary efficacy end point was carbon monoxide-confirmed self-reported abstinence during weeks 15 through 24. Secondary outcomes were carbon monoxide-confirmed self-reported abstinence for weeks 21 through 24 and weeks 21 through 52. The varenicline group (n = 760) had significantly higher continuous abstinence rates during weeks 15 through 24 vs the placebo group (n = 750) (32.1% for the varenicline group vs 6.9% for the placebo group; risk difference (RD), 25.2% [95% CI, 21.4%-29.0%]; relative risk (RR), 4.6 [95% CI, 3.5-6.1]). The varenicline group had significantly higher continuous abstinence rates vs the placebo group during weeks 21 through 24 (37.8% for the varenicline group vs 12.5% for the placebo group; RD, 25.2% [95% CI, 21.1%-29.4%]; RR, 3.0 [95% CI, 2.4-3.7]) and weeks 21 through 52 (27.0% for the varenicline group vs 9.9% for the placebo group; RD, 17.1% [95% CI, 13.3%-20.9%]; RR, 2.7 [95% CI, 2.1-3.5]). Serious adverse events occurred in 3.7% of the varenicline group and 2.2% of the placebo group (P = .07). Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment, and also at 1 year. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation. clinicaltrials.gov Identifier: NCT01370356.


Carcinogen: DNA adducts in tobacco smoke-associated cancer of the upper respiratory tract.
Mortality connected with tobacco smoke-associated laryngeal cancer in Poland markedly exceeds the relevant epidemiological data from other European countries. The main groups of genotoxic agents considered as potential carcinogens present in tobacco smoke are polycyclic aromatic hydrocarbons, aromatic amines, N-nitrosoamines and reactive oxygen species. Aromatic DNA adducts, N7-alkylated guanosines and oxidative DNA damage derived from tobacco smoke exposure were detected in laryngeal and oral (tumour and non-tumour) biopsies, and white blood cells of cancer subjects. Further, DNA lesions were analysed to estimate the significance of such confounders as intensity of smoking, subject's sex, age, topography of larynx, cancer staging and genetic factor. The number of cigarettes smoked per day was found to be the main determinant of an individual's DNA adduct level. The occurrence of DNA lesions was established as a reliable marker of former exposure to tobacco smoke genotoxicants. On the other hand, a comparison of DNA lesion levels in various regions of larynx indicates limited usefulness of DNA adduct analysis as an estimate of cancer risk. For a better risk estimation one has to take into account DNA lesions in proto-oncogenes and tumour suppressor genes and the efficacy of DNA repair. Altogether, DNA adducts formation and removal has to be considered as a single stage in the multistep carcinogenesis.


[Contancy of color perception in the grey toad].
Under the conditions of behavioural experiment capacity of grey toads for constant perception of an object colour was studied. It is shown that irrespective of the spectral composition of light source toad males are able to recomgnize blue colorations among the other ones (green and grey of various gradations).


Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.
Pitt-Hopkins syndrome (PTHS) is a rare developmental disorder associated with severe mental retardation, facial abnormalities, and intermittent hyperventilation. Autosomal dominant PTHS is caused by mutations in the transcription factor 4 (TCF4) gene, whereas NRXN1 and CNTNAP2 mutations are associated with autosomal recessive PTHS. To determine the impact of missense mutations on TCF4 function, we tested a panel of PTHS-associated mutations using a range of quantitative techniques. Mutations in the basic helix-loop-helix (bHLH) domain of TCF4 alter the subnuclear localization of the mutant protein and can attenuate homo- and heterodimer formation in homogenous time-resolved fluorescence (HTRF) assays. By contrast, mutations proximal to the bHLH domain do not alter the location of TCF4 or impair heterodimer formation. In addition, we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. Here we find variable, context-specific deficits in the ability of the different PTHS-associated TCF4 mutants to transactivate these promoters when coexpressed with different bHLH transcription factors. These data demonstrate that PTHS-associated missense mutations can have multiple effects on the function of the protein, and suggest that TCF4 may modulate the expression of NRXN1 and CNTNAP2 thereby defining a regulatory network in PTHS.


Health Service Use Among Chinese American Older Adults: Is There a Somatization Effect?
Somatization of depressive symptoms among Chinese American older adults remains understudied. This study aimed to identify whether the relationship between depressive symptoms and use of health services (ie, doctor visits, hospital, and emergency department) could be due to pain and whether acculturation played a role in the relations among depressive symptoms, pain, and health service use. Secondary data came from the Population Study of Chinese Elderly in Chicago that surveyed 3159 Chinese community-dwelling older adults in the greater Chicago area. The average age was 76.3 years (standard deviation = 8.4); 57.95% were female). Negative binominal models were used to identify the effects of depression and pain on each type of health service use, controlling for sociodemographics and health-related factors (eg, chronic illness). Depressive symptoms were assessed using the Patient Health Questionnaire-9; pain was assessed by self-reported pain severity. Participants were classified into low, moderate, and high acculturation groups based on acculturation scores. Depressive symptoms and pain were positively related to health service use on the bivariate level. For groups with both low and high acculturation levels, depression and pain each independently predicted more health service use, whereas for the group with a moderate acculturation level, the effect of somatization was substantialized. Depression largely influenced health service use independently and partially through pain for older Chinese Americans. The somatization tended to be only salient for the moderate acculturation group, calling for more research attention to the complicated effect of acculturation. J Am Geriatr Soc 67:S584-S589, 2019.


Development and Alpha-testing of a Stepped Decision Aid for Patients Considering Nonsurgical Options for Knee and Hip Osteoarthritis Management.
To develop an innovative stepped patient decision aid (StDA) comparing the benefits and harms of 13 nonsurgical treatment options for managing osteoarthritis (OA) and to evaluate its acceptability and effects on informed decision making. Guided by the Ottawa Decision Support Framework and the International Patient Decision Aid Standards, the process involved (1) developing a decision aid with evidence on 13 nonsurgical treatments from the 2012 American College of Rheumatology OA clinical practice guidelines; and (2) interviewing patients with OA and healthcare providers to test its acceptability and effects on knowledge and decisional conflict. The StDA helped make the decision explicit, and presented evidence on 13 OA treatments clustered into 5 steps or levels according to their benefits and harms. Probabilities of benefits and harms were presented using pictograms of 100 faces formatted to allow comparisons across sets of options. It also included a values clarification exercise and knowledge test. Feedback was obtained from 49 patients and 7 healthcare providers. They found that the StDA presented evidence in a clear manner, and helped patients clarify their values and make an informed decision. Some participants found that there was too much information and others said that there was not enough on each treatment option. This innovative StDA allows patients to consider both the evidence and their values for multiple options. The findings are being used to revise and plan future evaluation. The StDA is an example of how research evidence in guidelines can be implemented in practice.


Impact of radiation dose on patient-reported acute taste alteration in a prospective observational study cohort in head and neck squamous cell cancer (HNSCC).
Taste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in relation to patient-assessed taste impairment in a prospective cohort treated with intensity-modulated radiotherapy. All patients with locally advanced HNSCC and amenable to radical treatment were included. Chemotherapy-induced taste alteration scale (CITAS), EORTC QLQ-C30 and QLQ-HN43 questionnaires at baseline (T0), 3 weeks (T1) and 3 months (T2) after radiotherapy conclusion were used to assess taste impairment. Base of tongue, submandibular glands (SG), parotid glands (PG) and taste buds, along with anterior and medium third of the tongue, were considered as organs at risk and thus delineated according to consensus guidelines. The mean dose to the above-mentioned structures was correlated with patient-reported outcomes. Between September 2019 and November 2020, 33 patients were recruited, 31 of which analyzed. 71% had oropharyngeal carcinoma, mostly HPV-related (60%). All were treated with tomotherapy. 77.4% had concurrent cisplatin. Mean scores of general taste alterations, global health status and dry mouth and sticky saliva were assessed. The mean doses to the anterior third, medium third and base of the tongue were 23.85, 35.50 and 47.67 Gy, respectively. Taste buds received 32.72 Gy; right and left parotid 25 and 23 Gy; right and left submandibular glands 47.8 and 39.4 Gy. At univariate analysis, dysgeusia correlated with SG mean dose (95% CI 0-0.02 p = 0.05) and PG mean dose (95% CI 0-0.02 p = 0.05); dry mouth with mean dose to anterior (95% CI 0.03-1.47 p = 0.04) and medium third (95% CI 0.02-0.93 p = 0.04) of the tongue, to taste buds (95% CI 0.06-0.96 p = 0.03) and to SGs (95% CI 0.06-0.63 p = 0.02); pain mouth with mean dose to taste buds (95% CI 0-0.02 p = 0.04), to SGs (95% CI 0-0.03 p = 0.03) and to base tongue (95% CI 0-0.02 p = 0.02). Our analysis supports the influence of dose distribution on the development of TA in HNSCC patients. The contribution of dose to taste buds and tongue subvolumes remains unclear and worthy of further investigation.


Systematic Review and Metaanalysis of the Reproducibility of Patient Self-reported Joint Counts in Rheumatoid Arthritis.
To assess the reproducibility of patient-reported tender (TJCs) and swollen joint counts (SJCs) of patients with rheumatoid arthritis (RA) compared to trained clinicians. We conducted a systematic literature review and metaanalysis of studies comparing patient-reported TJCs and/or SJCs to clinician counts in patients with RA. We calculated pooled summary estimates for correlation. Agreement was compared using a Bland-Altman approach. Fourteen studies were included in the metaanalysis. There were strong correlations between clinician and patient TJCs (0.78, 95% CI 0.76-0.80), and clinician and patient SJCs (0.59, 95% CI 0.54-0.63). TJCs had good reliability, ranging from 0.51 to 0.85. SJCs had moderate reliability, ranging from 0.28 to 0.77. Agreement for TJCs reduced for higher TJC values, suggesting a positive bias for self-reported TJCs, which was not observed for SJCs. Our metaanalysis has identified a strong correlation between patient- and clinician-reported TJCs, and a moderate correlation for SJCs. Patient-reported joint counts may be suitable for use in annual review for patients in remission and in monitoring treatment response for patients with RA. However, they are likely not appropriate for decisions on commencement of biologics. Further research is needed to identify patient groups in which patient-reported joint counts are unsuitable.


Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activities in vivo.
Methods for the simultaneous polarization of multiple 13C-enriched metabolites were developed to probe several enzymatic pathways and other physiologic properties in vivo, using a single intravenous bolus. A new method for polarization of 13C sodium bicarbonate suitable for use in patients was developed, and the co-polarization of 13C sodium bicarbonate and [1-(13)C] pyruvate in the same sample was achieved, resulting in high solution-state polarizations (15.7% and 17.6%, respectively) and long spin-lattice relaxation times (T1) (46.7 s and 47.7 s respectively at 3 T). Consistent with chemical shift anisotropy dominating the T1 relaxation of carbonyls, T1 values for 13C bicarbonate and [1-(13)C] pyruvate were even longer at 3 T (49.7s and 67.3s, respectively). Co-polarized 13C bicarbonate and [1-(13)C] pyruvate were injected into normal mice and a murine prostate tumor model at 3T. Rapid equilibration of injected hyperpolarized 13C sodium bicarbonate with 13C CO2 allowed calculation of pH on a voxel by voxel basis, and simultaneous assessment of pyruvate metabolism with cellular uptake and conversion of [1-(13)C] pyruvate to its metabolic products. Initial studies in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model demonstrated higher levels of hyperpolarized lactate and lower pH within tumor, relative to surrounding benign tissues and to the abdominal viscera of normal controls. There was no significant difference observed in the tumor lactate/pyruvate ratio obtained after the injection of co-polarized 13C bicarbonate and [1-(13)C] pyruvate or polarized [1-(13)C] pyruvate alone. The technique was extended to polarize four 13C labelled substrates potentially providing information on pH, metabolism, necrosis and perfusion, namely [1-(13)C]pyruvic acid, 13C sodium bicarbonate, [1,4-(13)C]fumaric acid, and 13C urea with high levels of solution polarization (17.5%, 10.3%, 15.6% and 11.6%, respectively) and spin-lattice relaxation values similar to those recorded for the individual metabolites. These studies demonstrated the feasibility of simultaneously measuring in vivo pH and tumor metabolism using nontoxic, endogenous species, and the potential to extend the multi-polarization approach to include up to four hyperpolarized probes providing multiple metabolic and physiologic measures in a single MR acquisition.


Ophidian Spectaculitis and Spectacular Dysecdysis: A Histologic Description.
The histologic features of abnormal spectacles in 60 snakes from the 5 families of Boidae, Colubridae, Elapidae, Pythonidae, and Viperidae are described in a retrospective study conducted on specimens submitted to a private diagnostic service during a period of 15 years. Fifty-two snakes had inflammatory reactions in the spectacle. The stroma and outer epithelium of the spectacle were the layers most often involved in inflammatory disease. Lesions of the outer epithelium included edema, hyperkeratosis, and granulocyte infiltration occasionally with bacterial colonies and fungal elements. The stroma had infectious agents and inflammatory reactions in vessels and between the collagen fibrils. The inner epithelium had varying degrees of hyperplasia and hypertrophy, but no infectious agents were seen. Infectious agents in these cases included mites, bacterial disease, fungal disease, or a combination of bacterial and fungal disease. Special stains identified the bacteria most commonly involved to be Gram-positive cocci. Thirteen snakes had dysecdysis of the spectacle. Of these, 5 displayed a concurrent inflammatory reaction of the spectacle, while the remaining 8 snakes had extra keratin layers on a spectacle with an otherwise normal appearance. These keratin layers were attached to serocellular crusts located on the inner surface of the periocular scales. The cause for dyskeratotic lesions of the spectacle was not always apparent, and concurrent acariasis, other forms of dermatitis, trauma, suboptimal husbandry, and visceral disease were considered possible contributing factors. It was notable that only 4% of the submitted cases were found to have spectaculitis and/or spectacular dysecdysis.


Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates.
Fetal hypoxic-ischemic brain injury (HIBI) is a severe condition for which no effective therapy exists. In this study mesenchymal stem cells (MSCs) from human umbilical cord blood (UCB) of full-term newborns were isolated and intracerebrally transplanted into rat neonates after HIBI induction. Nerve function was assessed by the modified neurological severity scores (mNSS) to establish if MSCs could alleviate nerve injury. Immunostaining showed the transplanted MSCs migrated to the hippocampus. Rats receiving MSCs treatment showed significant improvement in the mNSS when compared with controls. Also, histochemical study showed alleviation of brain tissue injury after MSCs treatment. Differentiation of MSCs to astrocytes, but not neurons, was observed. The results indicate a beneficial effect of intracerebral transplantation of MSCs on the functional recovery of rat neonates with HIBI.


Identification, purification, and characterization of the type 4 fimbriae of Pasteurella multocida.
The presence of fimbriae on Pasteurella multocida has been reported, but there have been no prior studies aimed at conclusively characterizing these structures. We now report on the identification and characterization of type 4 fimbriae on serogroup A, B, and D strains of P. multocida. Under microaerophilic conditions P. multocida showed an increased expression of the fimbriae, which were observed to form bundles. Fimbriae purified by high-performance reverse-phase liquid chromatography constituted a single 18-kDa subunit, the first 21 amino acids of which shared very high similarity with the N-terminal amino acid sequence of other type 4 fimbrial subunits. Antiserum against the P. multocida 18-kDa protein immunostained the type 4 fimbrial subunit of Moraxella bovis and Dichelobacter nodosus. Based on these observations we conclude that P. multocida possesses type 4 fimbriae and have designated the P. multocida fimbrial subunit PtfA.


Clinical and pathological features of lipoleiomyoma of the uterine corpus: a review of 76 cases.
Uterine lipoleiomyoma is a rare and specific type of leiomyoma with a considerable amount of adipocytes. The aim of the study was to investigate the clinical, pathological and immunohistochemical features of lipoleiomyoma of the uterine corpus, and review its histogenesis and differential diagnosis from other neoplastic and non-neoplastic lesions in order to obtain a detailed profile of this somewhat uncommon lesion. Descriptive study. This study is a retrospective analysis of 70 consecutive women with 76 lipoleiomyomas, who underwent surgery mainly for uterine leiomyoma and gynecological carcinomas between January 2000 and April 2013. Clinical and pathological information was obtained from medical records. Immunohistochemistry was applied in selected cases. Parametric methods were used to compare clinical and pathologic features. The patients ranged in age from 34 to 77 years (mean 55.49 years). Lipoleiomyomas ranged from 0.5 to 55 cm in diameter (mean 5.50 cm). Typical macroscopic and microscopic features were noted. Sixty-nine (90.7%) tumors were in the uterine corpus and five (6.5%) were in the cervix. One broad ligament tumor and one retroperitoneal tumor were also studied. No tumors displayed cytologic atypia, mitosis, necrosis, calcification, or other degenerative changes. Immunohistochemically, the adipose tissue element was positive for vimentin, desmin, S100 protein, estrogen (ER), progesterone (PR), and Ki-67. Among patients with lipoleiomyomas, 53 cases (75.7%) had different types of lesions associated with hyperestrogenic status, such as adenomyosis, endometriosis, endometrial hyperplasia, and polyps, complex atypical endometrial hyperplasia, and gynecologic carcinomas. The follow-up period ranged from one to eight years (mean 4.6 years). There were no recurrences or tumor-related fatalities. In the present study, the lipoleiomyomas were seen more frequently in patients with adenomyosis, endometriosis, endometrial hyperplasia, polyps, and various gynecologic carcinomas. Lipoleiomyoma of the uterus seems to have a benign clinical course.


One positive impact of health care reform to physicians: the computer-based patient record.
The health care industry is an information-dependent business that will require a new generation of health information systems if successful health care reform is to occur. We critically need integrated clinical management information systems to support the physician and related clinicians at the direct care level, which in turn will have linkages with secondary users of health information such as health payors, regulators, and researchers. The economic dependence of health care industry on the CPR cannot be underestimated, says Jeffrey Ritter. He sees the U.S. health industry as about to enter a bold new age where our records are electronic, our computers are interconnected, and our money is nothing but pulses running across the telephone lines. Hence the United States is now in an age of electronic commerce. Clinical systems reform must begin with the community-based patient chart, which is located in the physician's office, the hospital, and other related health care provider offices. A community-based CPR and CPR system that integrates all providers within a managed care network is the most logical step since all health information begins with the creation of a patient record. Once a community-based CPR system is in place, the physician and his or her clinical associates will have a common patient record upon which all direct providers have access to input and record patient information. Once a community-level CPR system is in place with a community provider network, each physician will have available health information and data processing capability that will finally provide real savings in professional time and effort. Lost patient charts will no longer be a problem. Data input and storage of health information would occur electronically via transcripted text, voice, and document imaging. All electronic clinical information, voice, and graphics could be recalled at any time and transmitted to any terminal location within the health provider network. Hence, health system re-engineering must begin and be developed where health information is initially created--in the physician's office or clinic.


Necrotizing sialometaplasia: a sheep in wolf's clothing. Healing as a diagnostic test.
Necrotizing sialometaplasia is a benign self-limited intraoral lesion that is easily confused both clinically and histologically with squamous cell carcinoma. It presents as a painless ulceration, frequently on the hard palate, that histologically shows necrosis, inflammation, squamous metaplasia, and granulation tissue. It is thought to be due to infarction of minor salivary glands and heals spontaneously in six to 12 weeks. A brief period of observation for evidence of healing can be an important diagnostic clue in distinguishing this entity from cancer, thus saving the patient unnecessary surgery or radiation therapy.


Octreotide acetate-steroid combination therapy for malignant gastrointestinal obstruction.
The Aim of this study was to investigate improvements in symptoms caused by gastrointestinal obstruction following administration of octreotide acetate (Sandostatin®) injection through steroid and opioid administration. Patients (n=37) hospitalized with malignant gastrointestinal obstruction were enrolled in the present study. Twenty seven of them were investigated for gastrointestinal symptoms using the Japanese version of the Support Team Assessment Schedule (STAS-J). Octreotide acetate was administered intravenously to all 27 patients. Out of them, 17 showed a marked response, four a good response, and six no response. The overall response rate was 77.8%. Octreotide acetate with a steroid was administered to 19 patients; 13 showed a marked response, four a good response, and two no response at all. Multiple logistic regression analysis showed that that steroid administration improved the efficacy of octreotide acetate after adjusting for infusion dose (p=0.03). Intravenous administration of octreotide acetate with steroid can effectively improve gastrointestinal symptoms due to malignant gastrointestinal obstruction without adverse events.


Hyperbolic discounting and exponentiated demand: Modeling demand for cigarettes in three dimensions.
Behavioral economics has been a fruitful area of research in substance use. Mathematical descriptions of how individuals temporally discount the value of a commodity have been correlated with substance use and mathematical descriptions of drug consumption decreasing as a function of price (i.e., demand) predict maladaptive substance use. While there is a logical assumption that temporal factors affect demand for a drug, little has been done to merge these models. Thus, the purpose of this study was to combine models of discounting and demand, extending Howard Rachlin's work and contributions to novel areas of study. Data from 85 participants from Amazon Mechanical Turk (MTurk) who completed a hypothetical cigarette purchase task that included price of and delay to cigarettes were analyzed. Multilevel modeling was used to determine descriptive accuracy of combined additive and multiplicative models of discounting and demand. Of the discounting models used in conjunction with the exponentiated demand equation, the Rachlin hyperboloid best described the delay dimension of consumption. The multiplicative version of the Rachlin equation applied to both delay and price outperformed other models tested. Therefore, existing models of discounting and demand can be extended to modeling consumption data from complex multidimensional experimental arrangements.


A new standardized method for quantification of humic and fulvic acids in humic ores and commercial products.
Increased use of humic substances in agriculture has generated intense interest among producers, consumers, and regulators for an accurate and reliable method to quantify humic acid (HA) and fulvic acid (FA) in raw ores and products. Here we present a thoroughly validated method, the new standardized method for determination of HA and FA contents in raw humate ores and in solid and liquid products produced from them. The methods used for preparation of HA and FA were adapted according to the guidelines of the International Humic Substances Society involving alkaline extraction followed by acidification to separate HA from the fulvic fraction. This is followed by separation of FA from the fulvic fraction by adsorption on a nonionic macroporous acrylic ester resin at acid pH. It differs from previous methods in that it determines HA and FA concentrations gravimetrically on an ash-free basis. Critical steps in the method, e.g., initial test portion mass, test portion to extract volume ratio, extraction time, and acidification of alkaline extract, were optimized for maximum and consistent recovery of HA and FA. The method detection limits for HA and FA were 4.62 and 4.8 mg/L, respectively. The method quantitation limits for HA and FA were 14.7 and 15.3 mg/L, respectively.


Suicide and alcoholism. Interpersonal loss confirmed as a predictor.
We earlier reported that nearly one third of a consecutive series of 31 alcoholics who committed suicide had experienced loss of a close interpersonal relationship within six weeks or less of their death. In a replication study of 50 additional unselected alcoholic suicides, we found that 26% had experienced such loss within six weeks. As before, the distribution of such events was strikingly and significantly skewed toward the final weeks of the subject's life. This powerful confirmation gives added significance to such loss as a predictor of suicide among alcoholics.


Base J: discovery, biosynthesis, and possible functions.
In 1993, a new base, beta-d-glucopyranosyloxymethyluracil (base J), was identified in the nuclear DNA of Trypanosoma brucei. Base J is the first hypermodified base found in eukaryotic DNA. It is present in all kinetoplastid flagellates analyzed and some unicellular flagellates closely related to trypanosomatids, but it has not been found in other protozoa or in metazoa. J is invariably present in the telomeric repeats of all organisms analyzed. Whereas in Leishmania nearly all J is telomeric, there are other repetitive DNA sequences containing J in T. brucei and T. cruzi, and most J is outside telomeres in Euglena. The biosynthesis of J occurs in two steps: First, a specific thymidine in DNA is converted into hydroxymethyldeoxyuridine (HOMedU), and then this HOMedU is glycosylated to form J. This review discusses the identification and localization of base J in the genome of kinetoplastids, the enzymes involved in J biosynthesis, possible biological functions of J, and J as a potential target for chemotherapy of diseases caused by kinetoplastids.


Advancing CAR-based immunotherapies in solid tumors: CAR- macrophages and neutrophils.
Macrophages and neutrophils are the main components of the innate immune system and play important roles in promoting angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis in the tumor microenvironment (TME). They can also be harnessed to mediate cytotoxic tumor killing effects and orchestrate effective anti-tumor immune responses with proper stimulation and modification. Therefore, macrophages and neutrophils have strong potential in cancer immunotherapy. In this review, we briefly outlined the applications of macrophages or neutrophils in adoptive cell therapies, and focused on chimeric antigen receptor (CAR)-engineered macrophages (CAR-Ms) and neutrophils (CAR-Ns). We summarized the construction strategies, the preclinical and clinical studies of CAR-Ms and CAR-Ns. In the end, we briefly discussed the limitations and challenges of CAR-Ms and CAR-Ns, as well as future research directions to extend their applications in treating solid tumors.


CD150high CD4 T cells and CD150high regulatory T cells regulate hematopoietic stem cell quiescence via CD73.
Various extrinsic signals tightly control hematopoietic stem cell quiescence. Our recent study showed that hematopoietic stem cells are regulated by a special FoxP3+ regulatory T-cell population with high expression of a hematopoietic stem cell marker, CD150. Extracellular adenosine generated via a cell-surface ectoenzyme CD39 on CD150high regulatory T cells maintained hematopoietic stem cell quiescence. It remains unclear how conventional T cells and the other cell-surface ectoenzyme, CD73, contribute to regulation of hematopoietic stem cells. This work shows that CD150high regulatory T cells as well as unique CD150high CD4+ conventional T cells regulate hematopoietic stem cells via CD73. Global CD73 deletion increased the numbers of hematopoietic stem cells, cycling stem cell frequencies, and levels of reactive oxygen species in hematopoietic stem cells. In vivo antioxidant treatment inhibited the increase of hematopoietic stem cells in CD73 knockout mice, suggesting that CD73 maintains stem cell quiescence by preventing oxidative stress. High levels of CD73 expression were frequently found on CD150high regulatory T cells and CD150high FoxP3-CD4+ T cells within the bone marrow. Transfer of these CD150high regulatory T cells and CD150high CD4+ conventional T cells abolished the increase of hematopoietic stem cells in CD73 knockout mice. In addition, the increase of stem cells in CD73 knockout mice was also inhibited by pharmacological activation of adenosine receptor 2A which is highly expressed by hematopoietic stem cells. Taken together, these results suggest that CD73 of CD150high regulatory T cells and CD150high CD4+ conventional T cells protects hematopoietic stem cells from oxidative stress, maintaining stem cell quiescence via adenosine receptor 2A.


[Genetic effects of the gaseous phase of cigarette smoke on Saccharomyces cerevisiae].
The gaseous phase of cigarette smoke is active on Saccharomyces cerevisiae. A toxic effect and several genetic alterations were observed. Mitotic segregants are induced and the cytoplasmic "petite" mutation is selected and induced. These effects vary according to the growth phase of the culture and to the brand of cigarettes tested. Stationary phase cells are more resistant than exponentially growing ones.


Tricuspid Annular Plane Systolic Excursion (TAPSE) for the Assessment of Right Ventricular Function in Adult and Pediatric Cardiac Surgery: Modified Two-dimensional and M-mode TAPSE by Transesophageal Echocardiography Compared to M-mode TAPSE by Transthoracic Echocardiography.
To compare transesophageal echocardiography-guided 2-dimensional and M-mode tricuspid annular plane systolic excursion (TAPSE) to transthoracic echocardiography (TTE)-guided M-mode TAPSE in terms of accuracy, interobserver, and intra-observer variability. A prospective, observational study. Adult and pediatric operating rooms. Adult and pediatric patients (42 each) undergoing cardiac surgeries. None. Modified midesophageal (Mod-ME), deep transgastric, and transgastric TAPSEs were analyzed for reliability and were compared to TTE TAPSE in both adult and pediatric groups. Modified ME TAPSE showed good method agreement with TTE TAPSE (bias = -0.97, p = 0.08 (adult); bias = 0.17, p = 0.71 [pediatric]), and showed a moderate correlation with right ventricular (RV) fractional area change (FAC) (r = 0.41, p = 0.006, [adult]; r = 0.57, p < 0.001, [pediatric]), with acceptable interobserver variability (percentage error =10.56 [adult]; 4.42 [pediatric]) and intraobserver variability (percentage error = 13.1 [adults]; 12.24 [pediatric]). Transgastric TAPSE poorly agreed with TTE TAPSE and had higher interobserver and intraobserver variability. Deep transgastric TAPSE had good method agreement with TTE TAPSE and had acceptable interobserver and intra-observer variability. Modified ME TAPSE is a reliable and reproducible measure of RV function before pericardiotomy in both adult and pediatric cardiac surgery. Right ventricular FAC values reflected the RV systolic function better than TAPSE after pericardiotomy. Deep transgastric TAPSE is reliable and reproducible but is less accurate than Mod-ME TAPSE.


Immediate pigment darkening: description, kinetic and biological function.
Immediate pigment darkening (IPD) is a transitory darkening of the skin observed after UVA exposure. The melanocytic system is implicated in its development. Indeed, it involves structural changes in melanocytes and keratinocytes and a chemical modification of pre-existing melanin. Darkening intensity is maximum immediately after exposure and decreases rapidly. The maximum efficiency wavelength for induction of IPD is around 340 nm. The phenomenon is inhibited by oxygen deprivation. Dose-response curves are linear for doses above 4 J/cm2. Minimum dose for induction of IPD (MIPDD) varies with the subject according to phototype, melanotype and skin color. The best criterion for predicting MIPDD seems to be chromametrically determined skin color. The biological role of IPD remains poorly understood; several hypotheses are discussed.